Pyrrolobenzodiazepine Therapeutic Agents Useful in the Treatment of Leukemias

Abstract

A pyrrolobenzodiazepine dimer compound of Formula (I): or pharmaceutically acceptable salt or solvate thereof is useful as a therapeutic agent for the treatment of leukaemias, especially B-cell leukaemias, that exhibit resistance to other chemotherapeutic drugs, wherein: the dotted lines indicate the optional presence of a double bond between C1 and C2 or C2 and C3; R 2 and R 3 are independently selected from —H, ═O, ═CH 2 , —CN, —R, OR, halo, ═CH—R, O—SO 2 —R, CO 2 R and COR; R 6 , R 7 and R 9 are independently selected from II, R, OII, OR, SII, SR, NII 2 , NIIR, NRR′, nitro, Me 3 Sn and halo; where R and R′ are independently selected from optionally substituted C 1-12 alkyl, C 3-20 heterocyclyl and C 5-20 aryl groups; R 10 is a carbamate-based nitrogen protecting group and R 15 is either O—R 11 , wherein R is an oxygen protecting group, or OH, or R 10 and R 15 together form a double bond between N10 and C11; R″ is a C 3-12 alkylene group, which chain may be interrupted by one or more heteroatoms and/or aromatic rings, and each X is independently selected from 0, S, or NH; R 2′ , R 3′ , R 6′ , R 7′ , R 9′ , R 10′ and R 15′ are all independently selected from the same lists as previously defined for R 2 , R 3 , R 6 , R 7 , R 9 , R 10 and R 15 respectively.

1 - 10 . (canceled) 
     
     
         11 . A method of treatment of a patient suffering from leukaemia that exhibits drug resistance, comprising administering to said patient a therapeutically effective amount of a compound of formula I: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or solvate thereof, wherein:
 the dotted lines indicate the optional presence of a double bond between C1 and C2 or C2 and C3; 
 R 2  and R 3  are independently selected from —H, ═O, ═CH 2 , —CN, —R, OR, halo, ═CH—R, O—SO 2 p 13  R, CO 2 R and COR; 
 R 6 , R 7  and R 9  are independently selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NRR′, nitro, Me 3 Sn and halo; 
 where R and R′ are independently selected from optionally substituted C 1-12  alkyl, C 3-20  heterocyclyl and C 5-20  aryl groups; 
 R 10  is a carbamate-based nitrogen protecting group and R 15  is either O—R 11 , wherein R 11  is an oxygen protecting group, or OH, or R 10  and R 15  together form a double bond between N10 and C11; 
 R″ is alkylene group, which chain may be interrupted by one or more heteroatoms and/or aromatic rings, and each X is independently selected from  0 , S, or NH; 
 R 2′ , R 3′ , R 6′ , R 7′ , R 9′ , R 10′  and R 15′  are all independently selected from the same lists as previously defined for R 2 , R 3 , R 6 , R 7 , R 9 , R 10  and R 15  respectively. 
 
     
     
         12 . The method according to  claim 11 , wherein the leukaemia comprises a p53 mutation. 
     
     
         13 . The method according to  claim 11  or  claim 12 , wherein the drug resistance of the leukaemia is a result of prior administration of a chemotherapeutic agent. 
     
     
         14 . A method of treatment of a patient suffering from B-cell leukaemia wherein it is desired not to reduce the patient's T-cell count, comprising administering to said patient a therapeutically effective amount of a compound of formula I: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or solvate thereof, wherein:
 the dotted lines indicate the optional presence of a double bond between C1 and C2 or C2 and C3; 
 R 2  and R 3  are independently selected from —H, ═O, ═CH 2 , —CN, —R, OR, halo, ═CH—R, O—-SO 2 R, CO 2 R and COR; 
 R 6 , R 7  and R 9  are independently selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NRR′, nitro, Me 3 Sn and halo; 
 where R and R′ are independently selected from optionally substituted C 1-12  alky, , C 3-20  heterocyclyl and C 5-20  aryl groups; 
 R 10  is a carbamate-based nitrogen protecting group and R 15  is either O—R 11 , wherein R 11  is an oxygen protecting group, or OH, or R 10  and R 15  together form a double bond between N10 and c11; 
 R″ is a C 3-12  alkylene group, which chain may be interrupted by one or more heteroatoms and/or aromatic rings, and each X is independently selected from O, S, or NH; 
 R 2′ , R 3′ , R 6′ , R 7′ , R 9′ , R 10′  and R 15′  are all independently selected from the same lists as previously defined for R 2 , R 3 , R 6 , R 7 , R 9 , R 10  and R 15  respectively. 
 
     
     
         15 . The method according to  claim 14 , wherein the compound exhibits higher cytotoxicity for B-cells than for T-cells in cells from healthy patients and in cells from those suffering from B-cell chronic lymphocytic leukaemia. 
     
     
         16 . A method of treatment of a patient suffering from B-cell leukaemia wherein it is desired to selectively kill malignant B-cells, comprising administering to said patient a therapeutically effective amount of a compound of formula I: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or solvate thereof, wherein:
 the dotted lines indicate the optional presence of a double bond between C1 and C2 or C2 and C3; 
 R 2  and R 3  are independently selected from —H, ═O, ═CH 2 , —CN, —R, OR, halo, ═CH—R, O—SO 2 —R, CO 2 R and COR; 
 R 6 , R 7  and R 9  are independently selected from H, R, OH, OR, SH, SR, NH 2 NHR, NRR′, nitro, Me 3 Sn and halo; 
 where R and R′ are independently selected from optionally substituted C 1-12 , alkyl C 3-20  heterocyclyl and C 5-20  aryl groups; 
 R 10  is a carbamate-based nitrogen protecting group and R 15  is either O—R 11 , wherein R 11  is an oxygen protecting group, or OH, or R 10  and R 15  together form a double bond between N10 and C11; 
 R″ is a C 3-12  alkylene group, which chain may be interrupted by one or more heteroatoms and/or aromatic rings, and each X is independently selected from O, S, or NH; 
 R 2′ , R 3′ , R 6′ , R 7′ , R 9′ , R 10′  and R 15′  are all independently selected from the same lists as previously defined for R 2 , R 3 , R 6 , R 7 , R 9 , R 10  and R 15  respectively. 
 
     
     
         17 . The method according to  claim 16 , wherein the compound or pharmaceutically acceptable salt or solvate thereof shows a higher cytotoxicity towards malignant B-cell chronic lymphocytic leukaemia cells than towards normal B-cells. 
     
     
         18 . The method according to either  claim 11 ,  14  or  16 , wherein the compound has the formula: 
       
         
           
           
               
               
           
         
       
       or is a pharmaceutically acceptable salt or solvate thereof. 
     
     
         19 . The method according to  claim 11 ,  14  or  16 , wherein the leukaemia is B-cell chronic lymphocytic leukaemia.